The kidney has a dual importance in drug metabolism, first as an organ for the elimination of foreign compounds, and second as a target of drug toxicity. Two groups of antibiotics, the cephalosporins, and to a greater extent the aminoglycosides, are of particular importance in this respect. Both are eliminated largely by the kidney, and both are potentially nephrotoxic. Among the cephalosporins, cephaloridine is the most nephrotoxic; cefazolin is also mildly nephrotoxic, but at far greater doses. Although there is little or no cephaloridine secretion into the urine, this drug is transported into the proximal tubule by p-aminohippurate (PAH) secretory carrier. Both the transport and the proximal tubular toxicity of cephaloridine and cefazolin are inhibited by probenecid and other organic anions. Preliminary studies in this laboratory have demonstrated an inhibitory effect of cephaloridine on respiration by renal cortical mitochondria. Further studies are planned to further define the nature and the significance of this effect on renal and non-renal mitochondria (and on respiration by renal tubules) exposed to various cephalosporins and penicillins in vitro and in vivo. Work is also proposed to determine the extent and nature of any toxic interaction between cephalosporins and aminoglycosides. Because aminoglycosides may augment organic anion transport in the kidney, studies are proposed to compare the effect of aminoglycosides on cephaloridine transport and toxicity. Reports of aminoglycoside uptake by the kidney and of prevention of aminoglycoside toxicity by an organic and an inorganic anion have led to the design of further studies evaluating the relationship between renal aminoglycoside uptake and toxicity similar to those done previously in this laboratory with cephaloridine. Finally, we will evaluate the potential for toxic interaction between aminoglycosides and cephalosporins (and between potent diuretics and cephalosporins) on mitochondrial and renal tubule respiration.